Cutrone Lorenza, Djupenström Hedvig, Peltonen Jasmin, Martinez Klimova Elena, Corso Simona, Giordano Silvia, Sistonen Lea, Gramolelli Silvia
Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland.
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
PLoS Pathog. 2025 Apr 17;21(4):e1013108. doi: 10.1371/journal.ppat.1013108. eCollection 2025 Apr.
The Human gamma-herpesviruses Kaposi's sarcoma herpesvirus (KSHV) and Epstein-Barr virus (EBV) are causally associated to a wide range of cancers. While the default infection program for these viruses is latent, sporadic lytic reactivation supports virus dissemination and oncogenesis. Despite its relevance, the repertoire of host factors governing the transition from latent to lytic phase is not yet complete, leaving much of this complex process unresolved. Here we show that heat shock factor 2 (HSF2), a transcription factor involved in regulation of stress responses and specific cell differentiation processes, promotes gamma-herpesvirus lytic gene expression. In lymphatic endothelial cells infected with KSHV and in gastric cancer cells positive for EBV, ectopic HSF2 enhances the expression of lytic genes; While knocking down HSF2 significantly decreases their expression. HSF2 overexpression is accompanied by decreased levels of repressive histone marks at the promoters of the lytic regulators KSHV ORF50 and EBV BZLF1, both characterized by poised chromatin features. Our results demonstrate that endogenous HSF2 binds to the promoters of KSHV ORF50 and EBV BZLF1 genes and shifts the bivalent chromatin state towards a more transcriptionally permissive state. We detected HSF2 binding to the ORF50 promoter in latent cells, in contrast, in lytic cells, HSF2 occupancy at the ORF50 promoter is lost in conjunction with its proteasomal degradation. These findings identify HSF2 as a regulator of gamma-herpesvirus lytic gene expression in latency and offer new insights on the function of this transcription factors at poised gene promoters, improving our understanding of its role in differentiation and development.
人类γ-疱疹病毒卡波西肉瘤疱疹病毒（KSHV）和爱泼斯坦-巴尔病毒（EBV）与多种癌症存在因果关联。虽然这些病毒的默认感染程序是潜伏性的，但偶尔的裂解性再激活有助于病毒传播和肿瘤发生。尽管其具有相关性，但调控从潜伏阶段向裂解阶段转变的宿主因子库尚未完整，这使得这个复杂过程的许多方面仍未得到解决。在这里，我们表明热休克因子2（HSF2），一种参与应激反应调节和特定细胞分化过程的转录因子，可促进γ-疱疹病毒裂解基因的表达。在感染KSHV的淋巴管内皮细胞和EBV阳性的胃癌细胞中，异位表达的HSF2增强了裂解基因的表达；而敲低HSF2则显著降低其表达。HSF2的过表达伴随着裂解调节因子KSHV ORF50和EBV BZLF1启动子处抑制性组蛋白标记水平的降低，这两者都具有平衡染色质特征。我们的结果表明，内源性HSF2与KSHV ORF50和EBV BZLF1基因的启动子结合，并将二价染色质状态转变为更有利于转录的状态。我们在潜伏细胞中检测到HSF2与ORF50启动子结合，相反，在裂解细胞中，HSF2在ORF50启动子处的占据情况随着其蛋白酶体降解而丧失。这些发现确定HSF2是潜伏状态下γ-疱疹病毒裂解基因表达的调节因子，并为该转录因子在平衡基因启动子处的功能提供了新的见解，增进了我们对其在分化和发育中作用的理解。
